Microgranules based on active principle and method for making same

ABSTRACT

The invention concerns a microgranule consisting of a core coated with at least a coating layer, said coated core comprising at least an active principle. The invention is characterised in that the core and said coating layer contain each between 80 and 95 wt. % of active principle, the complement to 100% consisting of at least a binding agent, and the coated core has a substantially spherical shape. The invention also concerns the method for making such microgranules.

[0001] The invention relates to a microgranule consisting of a coatedcore comprising at least one active principle. It also relates to amethod for making said microgranule and to the pharmaceuticalcompositions containing a plurality of said microgranule.

[0002] The document WO 95/22319 describes a method for making byextrusion/spheronization fine particles based on an active principle.The fine particles obtained have a size of between 50 μm and 1 mm. Inparticular, the examples describe particles having a size equal to 300μm, comprising up to 72% of active principle in the presence of at leastthree excipients including in particular an extrusion agent. Inaddition, these same examples and in particular formula 1 c shows thatthis method does not make it possible to obtain fine particles of thisorder of size with a high concentration of active principle, equal to95%. Finally, the fine particles obtained at the end of the method havea surface which is too irregulator to allow subsequent satisfactorytreatment, the coating designed to mask the taste of the activeprinciple requiring, for example, a high level of coating.

[0003] The document EP-A-443572 describes a coating composition whichcan be applied in various forms and in particular microgranulesdesignated here by the expression “fine granules”. It is indicated thatat least 75% of the population of microgranules have a size of between 1and 500 μm. No information is given relating to the concentration ofactive principle in the microgranule.

[0004] The document FR-A-2 419 722 describes microgranules of activeprinciple and in particular of ferritin and their method of preparation.These microgranules consist of a core comprising a first coatingobtained by spraying an aqueous suspension of active principle, thecohesion of said first coating with the core being brought about byuniform dispersion, between each spraying step, of small quantities oftalc (see in particular page 7, example 3). The core thus coated has, inaddition, a second coating, whose nature depends on the characteristicsof release of the desired active principle. In practice, the core itselfcan have two different forms. Thus, in a first embodiment, the coreconsists exclusively of inert material, for example of the sucrose type.In a second embodiment, (example 3), the core exists in the form of agranule based on a binder (for example starch) and an active principlein ratios of 50/50.

[0005] The method of manufacture and the microgranule thus obtainedexhibit a number of disadvantages. As regards first of all the method ofmanufacture, it requires at least four steps, which are the manufactureof the core, and then, alternatively, the application of the firstcoating, and of the talc dispersion and finally the application of thesecond coating. Such a method is particularly long and cannot beperformed continuously. In addition, the cohesion of the first coatingonto the core is not always homogeneous, leading to coated cores havingan irregular surface and thereby increasing the quality of materialnecessary for the second coating. As regards the microgranule as such,it is indicated that the core before coating has a size of between 0.3and 0.5 millimeters (see examples) for a concentration of activeprinciple representing only 50% of the mass of the core.

[0006] Accordingly, the first problem which the invention proposes tosolve is to provide microgranules whose core, before coating of thefunctional layer(s) conferring on the microgranule the desiredcharacteristics of release of the active principle and/or of masking thetaste, is as concentrated as possible in active principle.

[0007] The second problem which the invention proposes to solve is toprovide a microgranule whose nucleus, before coating the functionallayer(s), is appreciably spherical so as to reduce its specific surfaceand thus reduce the quantity of material necessary for subsequentcoating.

[0008] The third problem which the invention proposes to solve is toprovide a microgranule whose nucleus, before coating the functionallayer(s), has a size which is as small as possible, advantageously amedian size of less than 500 μm.

[0009] The subject of the invention is therefore a microgranuleconsisting of a core coated with at least one coating layer, said coatedcore comprising at least one active principle.

[0010] This microgranule is characterized in that the core and saidcoating layer each contain between 80 and 95% by weight of activeprinciple, the balance for 100% consisting of at least one binder, andin that the coated core has a substantially spherical shape.

[0011] Below an active principle concentration of 80%, the microgranuletiter is not sufficient and the proportion of binder is too high,leading to the size of the microgranule being increased. For aconcentration greater than 95%, the cohesion between the particles ofactive principle is not satisfactory because of the extremely lowproportion of binder.

[0012] In a preferred embodiment, the core and the coating layer eachcontain 85 and 93%, advantageously 90% by weight of active principle.

[0013] In an advantageous embodiment, the balance for 100% by weight ofthe core and of the coating layer consists exclusively of a binder.

[0014] The choice of “binder” will be determined as a function not onlyof its capacity to bind the particles of active principle to each otherin the coated core, but also of the desired functional characteristicsof the coated core, whether in the presence or in the absence ofsubsequent functional coating. The expression “functionalcharacteristics” denotes in particular, but without limitation, theproperties of masking of taste and/or of release (modified or otherwise)of the active principle.

[0015] These characteristics depend:

[0016] on the one hand, on the physicochemical characteristics of thebinder used (solubility, permeability, glass transition temperature, andthe like);

[0017] and on the other hand, on the nature of the active principle(solubility, bitterness, and the like).

[0018] In other words, before any subsequent functional coating, themicrogranule of the invention already has specific characteristics thusmaking it possible to reduce the thickness of the subsequent coating andtherefore the size of the final microgranule.

[0019] In practice, the binder is chosen from the group comprising ethylcellulose, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC),hydroxypropyl methyl cellulose (HPMC), acrylic polymers, methacrylicpolymers, amonio-methacrylate copolymer, polyacrylate, methacrylic acidcopolymer and polyvinylpyrrolidone.

[0020] According to another characteristic, the binder contained in thecoating layer and that contained in the core may be identical ordifferent.

[0021] As already stated, another objective of the invention is toreduce the size of the coated microgranule before coating the optionalsubsequent functional layer. The high titer of the microgranules of theinvention makes it possible to partially fulfill this objective. Tofurther reduce the size of the microgranules, the size of the particlesof active principle varies between 10 and 30μ.

[0022] In practice, the size of the coated microgranules of theinvention before optional subsequent coating is less than 500 μm,advantageously between 200 and 300 μm.

[0023] Of course and as already stated, the coated core constituting themicrogranule of the invention may comprise an additional functionalcoating, in general of polymeric origin, whose nature will depend on thedesired characteristics of the final formulation and in particular ofmasking taste and/or of modified or unmodified release of activeprinciple.

[0024] Because of the specific method of production which will bedescribed later, the microgranules of the invention have, in addition,the advantage of being substantially spherical, thus having a reducedspecific surface area which makes it possible to coat a subsequent layerof raw material in reduced quantities compared with the knownmicrogranules of the prior art. This subsequent layer preferablycomprises a polymer whose application to the microgranules will make itpossible to obtain the desired final characteristics.

[0025] Moreover, the microgranules of the invention may be used invarious galenic forms such as in particular sachets, gelatin capsules,liquid suspensions, suspensions intended for reconstitution immediatelybefore use. They can also enter into the composition of tablets whichare orodispersible or not. In this regard, the reduced size of themicrogranules of the invention makes it possible to reduce theproportion of compression excipients (for example the diluents)necessary for producing a homogeneous mixture before compression, whichmakes it possible to have a final form of smaller size and weightcompared with known tablets of the same size and to also reduce thecompression forces.

[0026] In this regard, the invention relates more particularly to fastdisintegrating multiparticulate type tablets such as those described bythe applicant in the document FR-A-2 679 451, and fast dispersible typetablets comprising the microgranules described above.

[0027] The subject of the invention is also the method for making themicrogranules described above according to which:

[0028] in a first step, a granulation solution comprising at least onebinder in a solvent is sprayed onto the individualized particles ofactive principle maintained in suspension in a fluidized bed until acore is obtained;

[0029] and then, in a second step, the core formed is coated by sprayinga coating suspension or solution based on particles of active principleand binder, the coated core obtained then having a substantiallyspherical shape.

[0030] In an advantageous embodiment, a step for drying the coresobtained is intercalated between the first and the second step.

[0031] According to another characteristic, the method may be performedcontinuously or batchwise.

[0032] Of course, the solvent in which the binder is dissolved will bedetermined as a function of the actual nature of the binder and will bechosen from aqueous or organic solvents, alone or in combination.

[0033] To solve the problem posed of obtaining coated cores whose sizeis as small as possible, in any case below 500 micrometers, preferablybelow 350 micrometers, the size of the particles of active principleused in the first step is between 10 and 30 micrometers, advantageously25 micrometers, while the size of the particles of active principle usedin the second step is between 10 and 20 micrometers, advantageouslybelow 15 micrometers.

[0034] Of course, such sizes of particles of active principle may beobtained by any methods known to persons skilled in the art, inparticular micronization or grinding.

[0035] In an advantageous embodiment, the size of the particles ofactive principle used in the first step is identical to the size ofthose used in the second step.

[0036] To check, during the method of manufacture, the size of themicrogranules as a function of the titer of active principle, the activeprinciple/binder ratio is constant during the first and second steps,advantageously equal to 90/10. Consequently, the second step may bestopped as soon as the desired size of the microgranule, below 500 μm,has been reached.

[0037] According to another characteristic, in a third step, at leastone additional coating solution is sprayed, whose composition is chosenas a function of the characteristics of masking of taste and/or ofrelease of active principle desired.

[0038] As already stated, the method of the invention is formed in afluidized bed, advantageously by a bottom spray technique. Theparameters of the fluidized bed (pressure, spraying rate, and the like)do not exhibit particular characteristics and will be adjusted in thecustomary manner by persons skilled in the art.

[0039] The invention and the advantages resulting therefrom will emergemore clearly from the following exemplary embodiments given by way ofillustration and without limitation.

EXAMPLE 1 Manufacture of Microgranules of Ibuprofen

[0040] a) Composition of the Coated Core ibuprofen 1600 g HPMC 606*  160g

[0041] b) Preparation of the Granulating Solutions and CoatingSuspension

[0042] Granulating Solution

[0043] 40 g of HPMC 606 are introduced into 360 g of purified water,with stirring until complete dissolution of the hydroxymethyl propylcellulose is obtained.

[0044] Coating Suspension

[0045] 1 200 g of micronized ibuprofen (25μ) and 120 g of HPMC 606 in 3080 g of purified water are mixed together, with constant stirring untilcomplete dissolution of the hydroxypropyl methyl cellulose is obtained.

[0046] c) Manufacture of the Coated Core

[0047] 400 g of ibuprofen having a particle size equal to 25 micrometersare introduced into a fluidized bed apparatus of the GLATT GPCG 1 typeequipped with a Bottom Spray tank, while the active principle is kept ata temperature sufficient to avoid sticking together while the mass iskept moist.

[0048] The granulating solution prepared above is then sprayed until acore having a median particle size of about 100 micrometers is obtained.

[0049] After drying the core thus formed, the active principle-basedcoating suspension is continuously sprayed until a granule is obtainedwhich has a median particle size of between 250 and 300 micrometers.

[0050] d) Functional Coating

[0051] A polymeric dispersion of ethyl cellulose and HPMC and syloid isapplied to the coated core in order to mask the taste of the activeprinciple.

EXAMPLE 2 Manufacture of Microgranules of Tinidazole

[0052] a) Composition of the Coated Core tinidazole 1600 g Eudragit ® E100  160 g

[0053] b) Manufacture of the Coated Core

[0054] Example 1 is repeated, replacing HPMC with Eudragit® E 100 andpurified water with ethanol.

[0055] The Eudragit® is chosen as binder, but also for its function asagent masking the taste of the active principle, while allowing itsimmediate release. This thereby makes it possible to improve the maskingof the taste from the granulation step, before the optional functionalcoating step.

EXAMPLE 3 Manufacture of Microgranules of Doxycyclin

[0056] a) Composition of the Coated Core doxycyclin  15 kg PVP K90 1.5kg

[0057] b) Preparation of the Granulating Solutions and CoatingSuspension

[0058] Granulating Solution

[0059] Preparation of a granulating solution of PVP K90 at 5% (w/w) inethanol.

[0060] Coating Suspension

[0061] 25 kg of the solution of PVP K90 at 5% in ethanol obtained aboveare collected and 10 kg of doxycyclin (10μ) in 23.75 kg of ethanol areadded thereto.

[0062] c) Manufacture of the Coated Core

[0063] 5 kg of doxycyclin (10μ) are introduced into a fluidized bedapparatus of the GLATT GPCG5 type equipped with a bottom spray tank anda 12″ nozzle.

[0064] The granulating solution obtained above is then sprayed. Afterdrying the core thus formed, the active principle-based coatingsuspension is sprayed continuously until a granule having a medianparticle size of about 257 μm is obtained.

[0065] d) Functional Coating

[0066] A polymeric solution of Eudragit® E100 (manufactured by Röhm) at12.5% (w/w) in ethanol is sprayed on the coated cores. The equivalent of10% (w/w calculated as dry polymer) of the mass of the coated cores isapplied for masking taste.

[0067] The invention and the advantages resulting therefrom are clearlyevident from the description.

[0068] The possibility of making coated microgranules whose coated corehas a very small size, below 300 micrometers, facilitating thefunctional coating and subsequent forming, will be noted in particular.

1. A microgranule consisting of a core coated with at least one coatinglayer, said coated core comprising at least one active principle,characterized in that the core and said coating layer each containbetween 80 and 95% by weight of active principle, the balance for 100%consisting of at least one binder, and in that the coated core has asubstantially spherical shape, whose median size is less than 500 μm. 2.The microgranule as claimed in claim 1, characterized in that thebalance for 100% by weight of the core and of the coating layerconsisting exclusively of binder.
 3. The microgranule as claimed inclaim 1, characterized in that the binder contained in the core and thebinder contained in said coating layer are identical.
 4. Themicrogranule as claimed in claim 1, characterized in that the bindercontained in the core and the binder contained in said coating layer aredifferent.
 5. The microgranule as claimed in claim 1, characterized inthat the binder is chosen from the group comprising ethyl cellulose,hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC),hydroxypropyl methyl cellulose (HPMC), acrylic polymers, methacrylicpolymers, amonio-methacrylate copolymer, polyacrylate, methacrylic acidcopolymer and polyvinylpyrrolidone.
 6. The microgranule as claimed inclaim 1, characterized in that the size of the particles of activeprinciple varies between 10 and 30 μm.
 7. The microgranule as claimed inclaim 1, characterized in that the coated core comprises an additionalfunctional layer whose composition is chosen according to thecharacteristics of masking of taste and/or of release of activeprinciple desired.
 8. A fast disintegrating multiparticulate tabletcomprising microgranules which are the subject of claim
 1. 9. A fastdispersible tablet comprising microgranules which are the subject ofclaim
 1. 10. A suspension in dry or liquid form comprising themicrogranules which are the subject of claim
 1. 11. A gelatin capsulecomprising the microgranules which are the subject of claim
 1. 12. Amethod for making the microgranule which is the subject of claim 1,according to which: in a first step, a granulation solution comprisingat least one binder in a solvent is sprayed onto the individualizedparticles of active principle maintained in suspension in a fluidizedbed until a core is obtained; and then, in a second step, the coreformed is coated by spraying a coating suspension or solution based onparticles of active principle and binder, the coated core obtained thenhaving a substantially spherical shape.
 13. The method as claimed inclaim 13, characterized in that a step for drying the cores obtained isintercalated between the first step and the second step.
 14. The methodas claimed in claim 13, characterized in that the size of the particlesof active principle used in the first step is between 10 and 30micrometers, advantageously 25 micrometers while the size of theparticles of active principle used in the second step is between 10 and20 micrometers, advantageously below 15 micrometers.
 15. The method asclaimed in claim 13, characterized in that the size of the particles ofactive principle used in the first step is identical to that of theparticles used in the second step.
 16. The method as claimed in claim13, characterized in that the active principle/binder ratio is constantthroughout the first and second steps.
 17. The method as claimed inclaim 13, characterized in that the second step is performed until thedesired size of the coated microgranule is obtained.
 18. The method asclaimed in claim 13, characterized in that in a third step, at least oneadditional coating solution is sprayed whose composition is chosen as afunction of the characteristics of masking of taste and/or of release ofactive principle desired.